Compostos de coordenação com zinco, ácido valproico, diclofenaco e ibuprofeno: uma nova abordagem para a obtenção de fármacos

Abstract

Non-steroidal anti-inflammatory drugs or NSAIDs ares the largest and most widespread class of drugs and as a consequence the largest representation of the drug market in history. NSAIDs act as inhibitors of the cyclooxygenase enzymes or COX responsible for the production of inflammatory process intermediates, especially for pain sensation. Of note in this class are diclofenac (Diclof) and ibuprofen (Ibup), two non-specific COX 1 and COX 2 inhibitor NSAIDs drugs. Another widely used molecule is sodium valproate or Valp, a first-line drug in the treatment of partial and generalized seizures, bipolar disorders and treatment of migraines. Unlike NSAIDs, Valp acts on the central nervous system as a neurotransmitter gamma amino butyric acid (GABA) agonist. Nicotinamide or Nic is one of the components of vitamin B3 complex, a vitamin that regulates metabolic processes of energy production at the cellular level, reducing oxidative stress and inhibiting agent of inflammatory processes. Valp, Diclof and Ibup are carboxylic acids and have high affinity for transition metals and produce chemically stable coordinating compounds. This study aimed to synthesize three Zn2+ ternary complexes containing Valp, Diclof and Ibup linked to vitamin B3 (Nic), to determine chemical structures by Fourier transform infrared spectrophotometry (FTIR), high resolution mass spectrometry ESI-TOF-MS (+), nuclear magnetic resonance spectrometry (1HNMR and 13CNMR), UV-Vis spectrophotometry and monocrystal X-ray diffraction, evaluate in vitro free radical scavenge capabilities, interactivity with the double helix of the DNA by circular dichroism spectrometry, to evaluate the breaking capacity of plasmid DNA of Escherichia coli in dark conditions and UV photo activation and to determine the LD50 through acute toxicity against Artemia salina nauplii. The complexes were obtained by chemical synthesis in two reaction steps, obtaining the binary salts Zn2(Valp)4, Zn(Diclof)2 and Zn(Ibup)2 in step 1 from sodium valproate, potassium diclofenac and sodium ibuprofenate reacting with ZnCl2 in aqueous solution. Step 2 comprises obtaining the ternary complexes Zn(Valp)2(Nic)2 (1), Zn2(Diclof)4(Nic)2 (2) and Zn2 (Ibup)4(Nic)2 (3) by adding the vitamin B3 (Nic) to the binary salt in dimethylformamide (DMF) and ethanol, followed by crystallization. Complex 1 has been characterized as a mononuclear octahedral compound, while complexes 2 and 3 are binuclear molecules with penta coordinate spheres. All structures are unpublished, so their structures were confirmed with careful evaluation of spectroscopic data. The evaluation of antioxidant capacity against ABTS+• radical showed no measurable antioxidant activity for any of the complexes, nor for Nic ligand alone. The experiments of evaluation of complex-CT-DNA interaction by circular dichroism spectrometry indicated the existence of mutual electrostatic attraction with large groove interactions by the evidence of hypochromism and red shift in the spectral bands due to the helicity and the base pair stacking. All complexes exhibit similar activity in degree and intensity, but do not produce intercalations or chain breaks. Simulation experiments of E. coli plasmid breakdown with and without light induction analyzed by gel electrophoretic separation showed that all complexes do not induce single breaks (DNA FII) and double breaks (DNA FIII) without statistical difference in relation to those negative controls for a concentration range from 0 to 400 mol L-1. The acute toxicity experiment against A. salina showed that complexes 2 and 3 are tolerated by nauplii up to a concentration range of 0 to 1200 g mL-1 with lethality without statistical difference for negative controls and Nic alone. The complex 1 showed dose/response correlation from the concentration of 420 g mL-1, with calculated LD50 of 3953 g mL-1. The results of acute toxicity in vivo indicate that the three complexes have low acute toxicity and corroborate the results of interaction with CT-DNA and plasmid DNA.